Polychlorinated biphenyls (PCBs) are persistent organic pollutants that bio-accumulate in the food supply and resist environmental degradation. Studies of human populations near the most polluted sites have found learning, memory and motor impairments in children exposed during pregnancy and breast-feeding. Animal studies show that PCBs significantly alter dopamine concentrations in the brain and that toxicity may be mediated through the ryanodine receptor. Recent evidence suggests PCB exposures may increase the risk of Parkinson's Disease; [however, PCBs also have significant effects on cerebellar development and function.] Not all exposed individuals experience the same level of adverse health effects, indicating that genetic differences affect risk. Our previous studies in mice identified two genes that affect susceptibility to PCB-induced developmental neurotoxicity: the aryl hydrocarbon receptor (AHR) and cytochrome P450 1A2 (CYP1A2). AhrbCyp1a2(-/-) mice with a high-affinity AHR and lacking CYP1A2 showed deficits in spatial and non-spatial learning and memory following developmental PCB exposure while AhrbCyp1a2(+/+) mice were resistant. Our [published and new] preliminary data show motor deficits and [learning and memory deficits that vary by sex and genotype using a mixture of congeners with little to no activity toward the ryanodine receptor. Therefore, we hypothesize that [additional pathways contribute to PCB developmental neurotoxicity in addition to toxicity mediated by the ryanodine receptor. To test this hypothesis, we will use these three lines of mice to: 1.) Compare motor function in PCB-exposed offspring and corn oil-treated controls 2.) Assess gene expression changes and crosstalk in pathways associated with motor function. 3.) Quantify protein levels in brain regions essential to normal motor function.] PUBLIC HEALTH RELEVANCE: Significance: Polychlorinated biphenyls are persistent organic pollutants that are neurotoxic to the developing brain. Genetic differences can affect an individual's risk of adverse health effects from environmental toxicants. The proposed research is designed to identify neural pathways affected by PCB exposure and humans at highest risk of PCB developmental neurotoxicity using a mouse model that mirrors known genetic variations in humans.